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in The Biology Files
Interview with Brian Shoichet: aggregation-induced inhibition
Ok, now that we have gotten past the Nobel mania (or maybe not; go Somorjai), we can hopefully come back to real life. I was reading an interview with Brian Shoichet, who is one of the most promising stars in the areas of screening, docking, and structure-based design. He has gotten his fingers in many pies, both computational and experimental.
However, it was somebody's comment about the pharmaceutical industry thinking that "Shoichet deserves a heroes prize" that got me looking at his work, and I quickly learnt the reasons for that quote. As we all know, one of the biggest or perhaps the biggest problem facing HTS in industry is false positives. A lot of times, molecules that are found to be active in an assay fail to be active later. If industry could weed out such nuisances ahead of time, a lot of time, money and energy could be saved.
Shoichet, after a lot of interesting initiation and investigation, came up with one simple reason for why molecules may be showing false colours; because they form colloidal aggregates that somehow inhibit the proteins in the assay. If these are broken up say with detergent, the individual molecules no longer show activity. Thus, a relatively simple physical phenomenon is responsible for these molecules showing false activities. Such molecules were detected in earlier assays by some characteristics, mainly very steep dose-response curves and flat SAR; changes in structure usually causing very small changes in activity. They are also often promiscuous inhibitors. But nobody knew what was exactly happening and all the analysis was post-"mortem".
The first step in Shoichet's lab was the elucidation of this aggregation-induced inhibition. The aggregation can be detected with dynamic light scattering (DLS). The more challenging and useful step is to be able to come up with a list of chemical scaffolds that are likely to show this phenomenon, so that one can watch out for them beforehand. Before that, one would also need to know the exact mechanism of aggregation-based inhibition. In case of some molecules, there is some structural correlation, flat aromatic dye-like molecules being prone to aggregation for example by stacking. But many other scaffolds seem more diverse and at first glance show no common functionalities. Ths phenomenon is linked by common physical forces, not chemical ones. The details are not known but continue to be worked out.
Shoichet's lab continues to make progress, and he has recently come up with a screen for detecting such aggregation-based inhibitors (DOI: 10.1021/jm061317y). There are two major conclusions from the study; first, that breaking up aggregates with detergents can be a good way of identifying them, and secondly that aggregation may be a much more common phenomenon for false positives in screens than was thought before. This fact may be extremely significant for industry and could potentially save a lot of time, money and labour beforehand.
In other quite different work (DOI: 10.1038/nature05981), Shoichet also made the cover of Nature, when he used docking and structure-based design to predict the function for an enzyme whose function was unknown, based on substrate docking and analysis. The strategy used was quite clever; docking thousands of high-energy forms of metabolites rather than the metabolites themselves to know which ones would optimally interact with the active site. In this particular case, the "optimum interaction" pointed to a deamination, and the protein of unknown function indeed experimentally turned out to be a good deaminase.
All in all, a very promising chemist and I believe one to watch out for. Unfortunately, the interview itself is published in the journal Assay and Drug Development Technologies, not one which libraries usually subscribe to (I got it through ILL). But here's the DOI anyway (DOI: 10.1089/adt.2007.9996)
Also, again, check out his Colbert-style interview on youtube.
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Shoichet gave a seminar sometime last spring in our dept. I was convinced I was gonna catch my forty winks when I learnt of his general field of work. But surprise, surprise, it turned out to be one of the better talks I have sat for! Definitely someone to watch out for.
ReplyDeletequite! i look forward to hearing his talk/meeting him
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